The objective of Dr. Russell's research is to understand the role of insulin signaling in regulating mammalian lifespan. Fat specific insulin receptor knockout (FIRKO) mice are protected from obesity despite increased food intake, remain insulin sensitive as they age, are resistant to oxidative stress, and have a prolonged lifespan. Dr. Russell will investigate the roles of systemic insulin sensitivity vs. fat specific insulin resistance in the stress resistance and longevity phenotypes of FIRKO mice. He will also investigate the tissue specificity of increased energy expenditure and oxidative stress resistance in FIRKO mice and determine whether they are mechanistically linked. Finally, he will test whether knockout of adipocyte IR in adult animals, rather than during fetal life, will reproduce the beneficial changes seen in FIRKO mice. These studies will provide insight into the mechanisms of stress resistance and longevity in FIRKO mice and will determine whether blocking adipocyte insulin signalling has potential improving human health and longevity. The goal of this Career Development Award is to allow Dr. Russell to establish an independent research program on the role of insulin and adipocyte biology in regulating aging. In addition to the proposed research, he will undertake specialized training in the study of aging. Dr. Ronald Kahn is well suited to sponsor Dr. Russell because of his pioneering work in insulin signalling and his record as a mentor. Dr. Russell's primary focus on aging, rather than insulin signaling and diabetes, will help to distinguish him from his mentor. A committee of distinguished aging experts will assist Dr. Russell in building expertise in the field of aging, provide career guidance, and promote his development into an independent investigator. Lay summary: Permanently blocking the ability of insulin to act on the fat of mice before they are born increases their lifespan and makes them more resistant to certain toxins, while at the same time making them resistant to weight gain and diabetes. The purpose of this study is to learn more about how this occurs, and to determine whether blocking insulin signalling in fat has potential to improve human health and longevity.